The Alphavirus genus, family Togaviridae, includes viruses that are significant human pathogens. Chikungunya virus (CHIKV) is an arbovirus, transmitted between human and non-human primates by the bite of an infected mosquito vector. CHIKV periodically causes explosive epidemics in naive human populations in the African, Asian and American tropics. Since early 2005, a CHIKV epidemic has been responsible for over 1.5 million cases of CHIK fever in India and the Indian Ocean islands of Riunion, Mauritius, Madagascar and Seychelles. Furthermore, travelers returning to Europe, Canada and the United States from these areas have been diagnosed with the disease raising the possibility for outbreaks in other parts of the world. CHIK fever is rarely fatal, although the current epidemic is causing a higher than typical death toll. In adults, the infection resembles dengue fever, with acute febrile illness associated with excruciating muscle and joint pain. The symptoms of arthralgia/arthritis frequently persist for weeks or months later the initial illness has disappeared. However, the severity of disease is strongly age-dependent: infected children rarely develop arthritis, but commonly suffer febrile convulsions with possible associated neurologic sequelae and hemorrhagic manifestations. Although CHIKV causes severe human disease on an epidemic/pandemic scale, the pathogenesis of the virus remains largely uncharacterized, no licensed vaccine is available and the treatment of human infections is limited to supportive care. The objective of the proposed research is to provide an understanding of the mechanisms of virus/host interaction and thereby facilitate the subsequent design of therapeutics for the treatment of acute disease and vaccines for protection. These studies will be facilitated by the development of a genetically-defined pathogenesis model for CHIK, including a cDNA clone of two natural CHIKV isolates: the CHIKV-37997 strain isolated during an epidemic in Senegal, 1983 and the La Rhunion (CHIKV-LR) strain isolated on Riunion Island early in the current epidemic. We propose to develop murine pathogenesis models that accurately reproduce the etiologies of human CHIKV infection, both hemorrhagic and arthritogenic, by exploring virus virulence and host response. The specific aims of the application are: 1) To characterize the febrile response and hemorrhagic manifestations in fatal infection of suckling mice versus self-limiting disease in adults; 2) To characterize arthritogenic manifestations of CHIKV infection in non-fatal disease of older mice; and 3) To improve murine pathogenesis models by mouse-adaptation of CHIKV. We hypothesize that comparison of fatal to non-fatal infections will identify host- and virus-encoded determinants of disease severity. These determinants will provide targets for therapeutic intervention during acute infection, whether acquired from natural arthropod transmission or a biowarfare/bioterrorism attack.